Investigators within the Adult Cancer Core worked collaboratively to provide the first evidence of a gene-environment interaction related to one of the single locus, high penetrance genetic causes of cancer, by showing that long-term use of oral contraceptives (OCs) impacts substantially on penetrance of BRCA1 and BRCA2. Because of the huge public health and scientific implications of this finding, Core members decided to pursue this preliminary finding with a more definitive study. However, the relative rarity of BRCA1 and BRCA2 mutations, combined with the strong possibility that a family history of breast cancer might substantially affect OC use patterns, led to major methodologic and study design challenges. The Study Design and Statistical Methodology Core led by Dr. Thomas created an entirely new, cost effective study design to address this issue (and similar gene x environment questions). Several agencies (NCI and CBCRP) are co-funding this important effort.

A second study in Shanghai demonstrated that aflatoxins are a major cause of liver cancer and that they interact strongly with hepatitis B virus infections in risk determination. This work was important because it was one of the early studies in which a molecular exposure biomarker was shown to predict cancer risk and also represents one of the few established synergisms between exposures in cancer causation. Core members have pursued similar work on isothiocyanates (ITCs, derived primarily from cruciferous vegetables) and lung cancer in this ongoing prospective study of diet and cancer in Shanghai. A urinary biomarker of ITCs was utilized that had previously been validated as an index of dietary exposure in an independent study in Singapore. The work in Shanghai demonstrated a strong, inverse relationship between urinary ITCs and lung cancer risk. Moreover, as ITCs are metabolized by two glutathione S-transferases (GSTM1 and GSTT1) it was predicted that these substantial chemopreventive effects of ITCs might be limited to those who are deficient (homozygous null) in these enzymes. This hypothesis was clearly supported. A manuscript describing these findings, the first known study demonstrating an interaction between genetic susceptibility and diet in relation to lung cancer risk, is “in review” in JNCI (London SJ, Yuan J-M, Chung F-L, Gao Y-T, Coetzee GA, Ross RK, and Yu MC. Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms and lung cancer risk: a prospective study of men in Shanghai, China). This work was presented at the first Center retreat in November, 1999, and was the major stimulus for the formation of the new Center research focus group on Phase I and Phase 2 enzymes.

Other Core members have been conducting a large, molecular epidemiologic case-control study of bladder cancer in Los Angeles and Shanghai, China to determine why two populations with similar smoking habits, the main risk factor for bladder cancer, have more than a 3-fold difference in bladder cancer incidence. The preliminary results have demonstrated that, as predicted, individuals with N-acetyltransferase 2 “fast” genotypes (but not NAT1) and GSTM1 null genotypes (but not GSTT1 or GSTM1) have an increase in bladder cancer risk, effects which are entirely limited to smokers. As these two enzymes are known to be involved in activation and deactivation of smoking-related arylamines, these findings are as had been predicted, and provide another strong example of a gene x environment interaction. A manuscript describing these findings is being prepared. These results were also presented at the Center retreat, and during discussion it was noted that for a specific NAT2 genotype, there was a wide range of “phenotype” as measured by caffeine metabolites. The idea was raised that this could be an epigenetic phenomenon, perhaps due to gene silencing by methylation, a suggestion which provided the impetus for the creation of a new SCEHSC DNA Methylation research focus group. Methylation is an area of research in which several USC basic scientists have international reputations, so the Focus Group provides a mechanism for expanding the interdisciplinary nature of the Center.

The Adult Cancer Core continues to be very active in studies of environmental carcinogenesis. Selected activities of note on a cancer site-specific basis are summarized below.

Drs. Ross, Yu, and Coetzee are just completing a molecular epidemiologic case-control study of bladder cancer among Los Angeles County residents, which involved 1514 incident cases and an equal number of age-, sex-, race and neighborhood-matched population controls. In addition to confirming the previously studied quantitative effects of cigarette smoking on bladder cancer risk, they have shown that use of filtered versus non-filtered cigarettes, low-tar versus high-tar cigarettes, and patterns of inhalation had no effect on the overall smoking-bladder cancer association.

They had hypothesized that regular use of analgesics might be a risk factor for bladder cancer, given the established causal relationship between phenacetin and cancer of the renal pelvis which is derived from the same embryological structure and share the same transitional type of epithelium as the bladder. The data did not support sustained use of analgesics as a risk factor for bladder cancer. But more importantly, they provided the first set of epidemiological data in support of non-steroidal anti-inflammatory drugs (NSAIDs) as chemopreventive agents against bladder cancer, an hypothesis with substantial experimental support.

Although the possible association between hair dye use and bladder cancer risk has been much studied, previous investigations never examined exposure by types of chemicals used. This study was the first to demonstrate a statistically significant, and dose-dependent relationship between personal use of permanent hair dyes and risk; there was a 3-fold increased risk in women who dyed their hair at least monthly for 15 or more years.

Radiographic density of mammograms is a risk factor for breast cancer, however little is known about its determinants. Mammograms from 1,500 pairs of identical twins are being collected and density determined by computerized methods by Dr. Giske Ursin, modified from Wolfe. Information on exogenous risk factors, especially use of hormone replacement therapy, is collected by telephone interviews with the twins. Over 1,600 twins (800 pairs) have been interviewed and mammograms collected from about 1,300 of those (650 pairs).

In another study looking at the relationship of pesticide residues to breast cancer risk of black women, collected blood samples from 330 African-American breast cancer cases and an equal number of African-American controls were collected to evaluate the hypothesis that serum levels of p,p’-DDE (a metabolite of DDT) and PCBs (polychlorinated biphenyls) are associated with increased risk of breast cancer. all measurements of pesticide levels and of lipid levels in the blood samples have been completed. Investigators are about to embark on the statistical analyses of the data.